Tandem-controlled Lysosomal Assembly of Nanofibres Induces Pyroptosis for Cancer Immunotherapy

Overview

Journal Nat Nanotechnol

Specialty Biotechnology

Date 2025 Feb 18

PMID 39966684

Authors

Junya Zhang

YuXuan Hu

Xidan Wen

Zeyue Yang

Ziyi Wang

Zhiyuan Feng

He Bai

Qi Xue

Yinxing Miao

Tian Tian

Peng Zheng

Jingjing Zhang

Jie Li

Ling Qiu

Jing-Juan Xu

Deju Ye

Affiliations

Soon will be listed here.

Abstract

Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.

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